Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang W
PROVIDER: S-EPMC5661646 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
Publications
Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration.
Wang Wenqiu W Gawlik Katarzyna K Lopez Joe J Wen Cindy C Zhu Jie J Wu Frances F Shi William W Scheibler Samuel S Cai Huimin H Vairavan Ram R Shi Alexander A Haw Weldon W Ferreyra Henry H Zhang Ming M Chang Sherman S Zhang Kang K
Signal transduction and targeted therapy 20160916
Age-related macular degeneration (AMD) is characterized by complex interactions between genetic and environmental factors. Here we genotyped the selected 25 single-nucleotide polymorphisms (SNPs) in 983 cases with advanced AMD and 271 cases with intermediate AMD and build an AMD life-risk score model for assessment of progression from intermediate to advanced AMD. We analyzed the performance of the prediction model for geographic atrophy progressors or choroidal neovascularization progressors ve ...[more]
Similar Datasets
Project description:Age-related macular degeneration (AMD) is the most common cause of visual impairment among the elderly in developed countries, and its prevalence is thus increasing as the population ages; however, treatment options remain limited because the etiology and pathogenesis of AMD are incompletely defined. Recently, much progress has been made in gene discovery and mechanistic studies, which clearly indicate that AMD involves the interaction of multiple genetic and environmental factors. The identification of genes that have a substantial impact on the risk for AMD is not only facilitating the diagnosis and screening of populations at risk but is also elucidating key molecular pathways of pathogenesis. Pharmacogenetic studies of treatment responsiveness among patients with the "wet" form of AMD are increasingly proving to be clinically relevant; pharmacogenetic approaches hold great promise for both identifying patients with the best chance for vision recovery as well as tailoring individualized therapies.
| S-EPMC3002218 | biostudies-literature
Project description:PurposeTo expand our predictive models for progression to advanced stages of age-related macular degeneration (AMD) based on demographic, environmental, genetic, and ocular factors, using longer follow-up, time varying analyses, calculation of absolute risks, adjustment for competing risks, and detailed baseline AMD and drusen status.DesignProspective, longitudinal study.ParticipantsWe included 2937 individuals in the Age-Related Eye Disease Study, of which 819 subjects progressed to advanced AMD during 12 years of follow-up.MethodsCox proportional hazards regression analyses were performed to calculate hazard ratios for progression. Covariates included demographic and environmental factors, 6 variants in 5 genes, baseline macular drusen size, and presence and type of advanced AMD in 1 eye at baseline. To assess the ability of risk scores based on all covariates to discriminate between progressors and nonprogressors, an algorithm was developed and the area under the receiver operating characteristic curve (AUC) was calculated. To validate the overall model, the total sample was randomly subdivided into derivation and test samples. Another model was built based on the derivation sample and assessed for calibration and discrimination in the test sample. Sample sizes needed for testing new treatments in clinical trials were estimated based on models with and without genetic variables.Main outcome measuresProgression to advanced AMD, including geographic atrophy and neovascular disease.ResultsIn multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression. The AUC for progression at 10 years in the model with genetic factors, drusen size, and environmental covariates was 0.915 in the total sample. In the test sample, based on a model estimated from the derivation sample, the AUC was 0.908. The sample sizes needed for clinical trials were estimated to be lower when genetic susceptibility was considered.ConclusionsFactors reflective of nature and nurture were incorporated into an expanded algorithm for risk prediction, which performed very well in both derivation and test samples. Risk scores and predicted progression rates will be useful for AMD surveillance and for designing clinical trials.Financial disclosure(s)Proprietary or commercial disclosure may be found after the references.
| S-EPMC4097877 | biostudies-literature
Project description:To evaluate the independent and joint effects of genetic factors and environmental variables on advanced forms of age-related macular degeneration (AMD), including geographic atrophy and choroidal neovascularization, and to develop a predictive model with genetic and environmental factors included.Demographic information, including age at onset, smoking status, and body mass index, was collected for 1844 participants. Genotypes were evaluated for 8 variants in 5 genes related to AMD. Unconditional logistic regression analyses were performed to generate a risk predictive model.All genetic variants showed a strong association with AMD. Multivariate odds ratios were 3.52 (95% confidence interval, 2.08-5.94) for complement factor H, CFH rs1061170 CC, 4.21 (2.30-7.70) for CFH rs2274700 CC, 0.46 (0.27-0.80) for C2 rs9332739 CC/CG, 0.44 (0.30-0.66) for CFB rs641153 TT/CT, 10.99 (6.04-19.97) for HTRA1/LOC387715 rs10490924 TT, and 2.66 (1.43-4.96) for C3 rs2230199 GG. Smoking was independently associated with advanced AMD after controlling for age, sex, body mass index, and all genetic variants.CFH confers more risk to the bilaterality of geographic atrophy, whereas HTRA1/LOC387715 contributes more to the bilaterality of choroidal neovascularization. C3 confers more risk for geographic atrophy than choroidal neovascularization. Risk models with combined genetic and environmental factors have notable discrimination power.Early detection and risk prediction of AMD could help to improve the prognosis of AMD and to reduce the outcome of blindness. Targeting high-risk individuals for surveillance and clinical interventions may help reduce disease burden.
| S-EPMC4134685 | biostudies-literature
Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the United States and developed countries. Although the etiology and pathogenesis of AMD remain unknown, a complex interaction of genetic and environmental factors is thought to exist. The incidence and progression of all of the features of AMD are known to increase significantly with age. The tendency for familial aggregation and the findings of gene variation association studies implicate a significant genetic component in the development of AMD. This review summarizes in detail the AMD-related genes identified by studies on genetically engineered and spontaneously gene-mutated (naturally mutated) animals, AMD chromosomal loci identified by linkage studies, AMD-related genes identified through studies of monogenic degenerative retinal diseases, and AMD-related gene variation identified by association studies.
| S-EPMC1950336 | biostudies-literature
Project description:The aim of the present study was to analyze the relationship of age-related macular degeneration (AMD) progression with clinical characteristics, demographic, and environmental risk factors that would affect disease development. In addition, the influence of three genetic AMD polymorphisms (CFH Y402H, ARMS2 A69S, and PRPH2 c.582-67T>A) on AMD progression was investigated. In total, 94 participants with previously diagnosed early or intermediate AMD in at least one eye were recalled for an updated re-evaluation after 3 years. The initial visual outcomes, medical history, retinal imaging data, and choroidal imaging data were collected to characterize the AMD disease status. Among the AMD patients, 48 demonstrated AMD progression, and 46 showed no disease worsening at 3 years. Disease progression was significantly associated with worse initial visual acuity (OR = 6.74, 95% CI = 1.24-36.79, p = 0.03) and the presence of the wet AMD subtype in fellow eyes (OR = 3.79, 95%CI = 0.94-15.2, p = 0.05). In addition, a higher risk of AMD progression appeared in the patients with active thyroxine supplementation (OR = 4.77, CI = 1.25-18.25, p = 0.002). The CC variant of CFH Y402H was associated with AMD advancement compared to the TC+TT phenotype (OR = 2.76, 95% CI: 0.98-7.79, p = 0.05). Identifying risk factors of AMD progression may lead to earlier intervention and better outcomes, preventing the expansion of the late stage of the disease.
| S-EPMC10004408 | biostudies-literature
Project description:Age related macular degeneration (AMD) is the leading cause of blindness in individuals older than 65 years of age. It is a multifactorial disorder and identification of risk factors enables individuals to make lifestyle choices that may reduce the risk of disease. Collaboration between geneticists, ophthalmologists, and optometrists suggests that genetic risk factors play a more significant role in AMD than previously thought. The most important genes are associated with immune system modulation and the complement system, e.g., complement factor H (CFH), factor B (CFB), factor C3, and serpin peptidase inhibitor (SERPING1). Genes associated with membrane transport, e.g., ATP-binding cassette protein (ABCR) and voltage-dependent calcium channel gamma 3 (CACNG3), the vascular system, e.g., fibroblast growth factor 2 (FGF2), fibulin-5, lysyl oxidase-like gene (LOXL1) and selectin-P (SELP), and with lipid metabolism, e.g., apolipoprotein E (APOE) and hepatic lipase (LIPC) have also been implicated. In addition, several other genes exhibit some statistical association with AMD, e.g., age-related maculopathy susceptibility protein 2 (ARMS2) and DNA excision repair protein gene (ERCC6) but more research is needed to establish their significance. Modifiable risk factors for AMD should be discussed with patients whose lifestyle and/or family history place them in an increased risk category. Furthermore, calculation of AMD risk using current models should be recommended as a tool for patient education. It is likely that AMD management in future will be increasingly influenced by assessment of genetic risk as such screening methods become more widely available.
| S-EPMC3880448 | biostudies-other
Project description:PURPOSE:Age-related macular degeneration (AMD) is a degenerative disease of the macula, often leading to progressive vision loss. The rate of disease progression can vary among individuals and has been associated with multiple risk factors. In this review, we provide an overview of the current literature investigating phenotypic, demographic, environmental, genetic, and molecular risk factors, and propose the most consistently identified risk factors for disease progression in AMD based on these studies. Finally, we describe the potential use of these risk factors for personalised healthcare. RECENT FINDINGS:While phenotypic risk factors such as drusen and pigment abnormalities become more important to predict disease progression during the course of the disease, demographic, environmental, genetic and molecular risk factors are more valuable at earlier disease stages. Demographic and environmental risk factors such as age and smoking are consistently reported to be related to disease progression, while other factors such as sex, body mass index (BMI) and education are less often associated. Of all known AMD variants, variants that are most consistently reported with disease progression are rs10922109 and rs570618 in CFH, rs116503776 in C2/CFB/SKIV2L, rs3750846 in ARMS2/HTRA1 and rs2230199 in C3. However, it seems likely that other AMD variants also contribute to disease progression but to a lesser extent. Rare variants have probably a large effect on disease progression in highly affected families. Furthermore, current prediction models do not include molecular risk factors, while these factors can be measured accurately in the blood. Possible promising molecular risk factors are High-Density Lipoprotein Cholesterol (HDL-C), Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), zeaxanthin and lutein. SUMMARY:Phenotypic, demographic, environmental, genetic and molecular risk factors can be combined in prediction models to predict disease progression, but the selection of the proper risk factors for personalised risk prediction will differ among individuals and is dependent on their current disease stage. Future prediction models should include a wider set of genetic variants to determine the genetic risk more accurately, and rare variants should be taken into account in highly affected families. In addition, adding molecular factors in prediction models may lead to preventive strategies and personalised advice.
| S-EPMC7155063 | biostudies-literature
Project description:PurposeTo analyze the correlations between age-related macular degeneration (AMD) and genetic and environmental risk factors for in a Brazilian population.DesignCross-sectional study with a control group.MethodsWe collected data on 236 participants 50 years of age or older (141 with AMD and 95 controls without the disease). Data was obtained using a questionnaire and included information on demographics, ocular and medical history, family history of AMD, lifestyle, and smoking and drinking habits. Genetic evaluations included direct sequencing for the LOC387715 (rs10490924) variant, as well as PCR and enzymatic digestion for the CFH Y402H (rs1061170) and HTRA1 (rs11200638) variants. We performed a risk assessment of environmental risk factors and genetic variants associated with AMD and determined correlations between AMD and the data collected using multiple linear regression analysis.ResultsOf the 141 AMD cases, 99 (70%) had advanced AMD in at least one eye (57% neovascular AMD and 13% geographic atrophy), and 42 (30%) had not-advanced AMD. Family history of AMD (OR: 6.58; 95% CI: 1.94-22.31), presence of cardiovascular disease (CVD) (OR: 2.39; 95% CI: 1.08-5.28), low physical activity level (OR: 1.39; 95% CI: 0.82-2.37), and high serum cholesterol (OR: 1.49; 95% CI: 0.84-2.65) were associated with an increased risk for AMD. There was a significant association between CVD and incidence of advanced AMD (OR: 2.29; 95% CI 0.81-6.44). The OR for the risk allele of the LOC387715 gene, the CFH gene and the HTRA1 gene were 2.21 (95% CI: 1.47-3.35), 2.27 (95% CI: 1.52-3.37), and 2.76 (95% CI: 1.89-4.03), respectively. In the stepwise multiple linear regression analyses, the HTRA1 and CFH risk alleles, family history of AMD, the LOC387715 risk allele, and CVD were associated with an increased risk of AMD for a total of 25.6% contribution to the AMD phenotype.ConclusionsThe analysis correlating environmental and genetic risk factors such as family history of AMD, and CVD and the variants of HTRA1, CFH, and LOC387715 genes showed an expressive contribution for the development of AMD among this admixed population.
| S-EPMC9165864 | biostudies-literature
Project description:Sphingolipids are bioactive molecules associated with oxidative stress, inflammation, and neurodegenerative diseases, but poorly studied in the context of age-related macular degeneration (AMD), a prevalent sight-threatening disease of the ageing retina. Here, we found higher serum levels of hexosylceramide (HexCer) d18:1/16:0 in patients with choroidal neovascularization (CNV) and geographic atrophy (GA), two manifestations of late stage AMD, and higher ceramide (Cer) d18:1/16:0 levels in GA patients. A sensitivity analysis of genetic variants known to be associated with late stage AMD showed that rs1061170 (p.Y402H) in the complement factor H (CFH) gene influences the association of Cer d18:1/16:0 with GA. To understand the possible influence of this genetic variant on ceramide levels, we established a cell-based assay to test the modulation of genes in the ceramide metabolism by factor H-like protein 1 (FHL-1), an alternative splicing variant of CFH that also harbors the 402 residue. We first showed that malondialdehyde-acetaldehyde adducts, an oxidation product commonly found in AMD retinas, induces an increase in ceramide levels in WERI-Rb1 cells in accordance with an increased expression of ceramide synthesis genes. Then, we observed that cells exposed to the non-risk FHL-1:Y402, but not the risk associated variant FHL-1:H402 or full-length CFH, downregulated ceramide synthase 2 and ceramide glucosyltransferase gene expression. Together, our findings show that serum ceramide and hexosylceramide species are altered in AMD patients and that ceramide levels may be influenced by AMD associated risk variants.
| S-EPMC6071970 | biostudies-literature
Project description:Worldwide, age-related macular degeneration (AMD) is a serious threat to vision loss in individuals over 50 years of age with a pooled prevalence of approximately 9%. For 2020, the number of people afflicted with this condition is estimated to reach 200 million. While AMD lesions presenting as geographic atrophy (GA) show high inter-individual variability, only little is known about prognostic factors. Here, we aimed to elucidate the contribution of clinical, demographic and genetic factors on GA progression. Analyzing the currently largest dataset on GA lesion growth (N = 388), our findings suggest a significant and independent contribution of three factors on GA lesion growth including at least two genetic factors (ARMS2_rs10490924 [P < 0.00088] and C3_rs2230199 [P < 0.00015]) as well as one clinical component (presence of GA in the fellow eye [P < 0.00023]). These correlations jointly explain up to 7.2% of the observed inter-individual variance in GA lesion progression and should be considered in strategy planning of interventional clinical trials aimed at evaluating novel treatment options in advanced GA due to AMD.
| S-EPMC4427438 | biostudies-literature